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T helper cell commitment


Naïve CD4+ T helper precusor cells differentiate along a T helper 1(Th1) and T helper 2 (Th2) pathway subsets. These two subsets of Th cells are defined by the patterns of cytokines they produce: Th1 (IFN-γ , IL-2) and Th2 (IL-4, 5, 6, 9, 10, 13). This differentiation is highly dependent on the presence of certain cytokines and their downstream signalling transcription factors.

The interleukin-4 and interleukin-12 direct the development of Th2 and Th1 subsets from a naïve CD4+ T cell.

c- Maf is a Th2-specific basic region/leucine zipper protein (protooncogene) that transactivates the IL-4 promoter in vitro.

NIP45 is a NFAT-interacting protein.

Bcl6 is a transcription factor which may compete with Stat6 to control the development of the Th2 lineage.

NFAT : there are 4 known NFAT proteins, three of the four are expressed in both Th1 and Th2. NFATc seems to have an activator role in controlling Th2 development and regulation, with, in contrast, a repressor role for NFATp and NFAT4. NFATc is present in alternatively spliced isoforms that differ in naïve and activated T cells.
Known NFAT target genes include:

GATA3 is a critical regulator of both early T cell development and the transition of a mature Th precursor cell to the Th2 lineage, consistent with the presence of GATA3-binding sites in the promoters of many T cell specific genes.
Upon activation naïve CD4+ T cells differentiate into T helper (Th) 1 or Th2 cells which are characterized by distinct cytokine expression patterns: Th1 cells secrete interleukin (IL)-2 and interferon-γ (IFN-γ ) to promote cellular immunity, while Th2 cells produce IL-4 and IL-5 to trigger predominantly humoral immunity. The cytokines required for Th cell differentiation have been defined, IL-12 inducing Th1, and IL-4 stimulating Th2 cell differentiation. For Th2 cell differentiation IL-4 signalling via Stat6 is essential. In addition, c-maf is a Th2 cell-specific transcription factor that induces IL-4 expression by activating the IL-4 promotor. Endogenous IL-4 gene expression can be induced in nonproducer cells by transfection of c-maf in combination with NFAT and NIP-45. GATA-3 is also a Th2 cell-specific transcription factor which does not directly regulate IL-4 transcription, but is clearly needed for IL-5 transcription. Activation of transcription factor Stat4 by IL-12 only occurs in IL-12Rβ 2-expressing Th1 cells. Development of Th1 cells is ablated in mice lacking either functional Stat4 that operates downstream of IL-12 signalling or transcription factor IRF-1 which regulates expression of IFN-γ and its target genes. The transcription factor ERM was reported to be expressed specifically in Th1 cells; however, it cannot induce IFN-γ production in Stat4-deficient cells. On the other hand, the stress-activated JNK and p38 kinase pathways and possibly their downstream transcription factor AP-1 are also thought to be involved in Th1 cell development.